Fluorinating polymer surfaces

ABSTRACT

Surfaces of polymers, particularly polyesters, can be fluorinated by deposition of a fluorocarbon from solution. The fluorocarbon may be an amorphous fluoropolymer, such as the copolymer of tetrafluoroethylene and bis-2,2-trifluoromethyl-4,5-difluoro-1,2-dioxole sold under the trademark TEFLON AF®, which is soluble in fluorinated alkanes and other fluorinated liquids such as those sold under the trademark FLUORINERT®. Surface-fluorinated polyesters, particularly in knitted fabric form, are useful as vascular grafts: the fluorinated surface reduces thrombogenicity and complement activation. The disadvantages of known surface fluorination methods, such as the cold plasma or glow discharge process, are avoided.

The subject of this invention is a process for modifying a surface on apolymer by forming a fluorinated surface on the polymer.

It frequently happens that an article made from a polymer which isparticularly suitable for making that article displays undesirablecharacteristics or side effects when used in the environment to whichthe article is exposed. These characteristics may spring from so-called"active" atoms, which may principally be hydrogen or oxygen atoms,present in the molecules of a polymer. Vascular grafts are a case inpoint. Polymers in general, and polyesters in particular, are among themost suitable materials for use in making such a graft. Polymers such aspolyester are, however, thrombogenic when exposed to blood as of coursethey are when used to form a vascular graft.

Blood platelets tend to adhere to the polymer and initiate bloodclotting. Polymers such as polyester are also known to activate theblood complement system. This is undesirable as complement activation isone of the first stages of an inflammatory response to foreign material.There is therefore a need to modify the polymer surface to reduce itsthrombogenicity and/or to reduce its platelet adhesion characteristics.

It has previously been proposed to eliminate or reduce the undesiredsurface activity of a polymer by fluorinating the polymer or at leastits surface; this has been explained as replacing the active atoms inthe polymer molecules, at the surface at least, by fluorine atoms.

One previously proposed method of fluorinating the surface of a polymeris disclosed in U.S. Pat. No. 4,264,750 and U.S. Pat. No. 4,404,256 andcomprises exposing the polymer to a cold plasma containing ions and/orradicals of a fluorine-containing substance under conditions to causesubstitution of hydrogen and/or other active atoms at the surface of thepolymer with fluorine atoms. Other, similar, processes require thedeposition of a thin layer of a fluoropolymer formed from the gaseousmonomer through plasma discharge (Yasuda et al, Biomat., Med. Dev., Art.Org., 4(3&4), 307-372 (1976) and Fowler et al, The Third WorldBiomaterials Congress, 21st to 25th Apr. 1988, Kyoto, Japan, Abstracts2C1-35, page 99).

The known plasma and glow discharge processes require very closecontrol, not only to provide effective fluorination but also to minimisethe degradation of the polymer which always takes place as a result ofsuch a treatment. It is also difficult to ensure a consistent surfacecoverage over all the bare polymer and, in the case of plasmapolymerisation, the chemical structure of the deposited polymer is proneto variability and hence to having a hererogenous structure.

It might be thought that the problem could be avoided simply bypreparing articles such as vascular grafts from a fluoropolymer, such aspolytetrafluoroethylene (PTFE). In practice, however, this is not thecase. Fabric grafts, particularly knitted ones, are preferred to thosemade of continuous, or microporous, material, to allow better tissueingrowth once the graft is in situ in the patient. PTFE fabric graftsare prone to fraying as a result of yarn slippage caused by the lowcoefficient of friction of PTFE; this is an important consideration asfraying can cause the disruption of a sutured attachment of a graft tothe host blood vessel.

The problem therefore still remains, and the present invention seeks toaddress it. It has now been found that a fluorine-containing layer canbe deposited on a polymer without the need for the complexphysico-chemical conditions of a plasma discharge process: instead, afluoropolymer can be deposited from solution onto the underlyingpolymer.

According to a first aspect of the present invention, there is thereforeprovided a process for forming a fluorinated surface on a polymer, theprocess comprising dissolving a fluorocarbon in a solvent for thefluorocarbon, bringing the resulting solution into contact with thepolymer and removing the solvent from the polymer.

By means of the invention, the polymer may present a non-active surface,for example a non-thrombogenic surface and/or anon-complement-activating surface. Alternatively or in addition, theremay be little or no diffusion of fluorine-containing material into thebulk of the polymer, thus avoiding degradation of the polymer andpreserving its original strength.

The term "fluorinated surface" should not be taken to imply thatnecessarily every single atom exposed at the surface is a fluorine atom.Rather, there will simply be a higher proportion of fluorine atoms atthe surface, after the process of the present invention has been appliedto a polymer.

By means of the invention, fluorinated surfaces can be applied to a widevariety of polymers (including polymer mixtures) for a correspondinglywide variety of uses. The invention has particular application, though,in the modification of polymers for use in surgically graftablematerial, particularly vascular grafts. Polyethylene and polypropylene,both of which are available from Montedison in yarn form, may be foundto be suitable, but the most preferred polymers for use in vasculargrafts are polyesters, particularly those sold under the trade marksKODAR (Kodak) TERYLENE (ICI) and DACRON (DuPont). Polyesters include butare not limited to polyethylene terephthalates (PETs) of general formulaI: ##STR1## in which R represents a hydrogen atom or a C₁ -C₄ alkoxygroup (such as a methoxy group) and n represents an integer or othernumber indicative of the degree of polymerisation of the polymer. Thepolyester sold by DuPont Speciality Polymers Division (Wilmington, Del.,USA) under the trade mark and designation DACRON TYPE 56 is the mostpreferred.

The physical form of the polymer will also vary depending on the natureand intended use of the article into which the polymer is (or is to be)made. For example, the polymer may be in the form of a sheet, film,strip, tube, shaped article, fabric piece (woven, knitted or other) orfabric article. Graftable materials, particularly vascular grafts, arepreferably made from fabric, which for best results should be knittedrather than woven. For such materials, it is generally preferred for theprocess of the invention to be applied to the fabric piece or fabricarticle, rather than to the yarn from which the piece or article ismade: in this way the problem of the modified surface being abraded whenthe yarn is woven or knitted is avoided. However, under somecircumstances it may well be acceptable or even desirable for the yarnitself to be treated by the process of the invention.

The fluorocarbon which is coated onto the polymers by means of theprocess of the invention is preferably, but not necessarily, afluoropolymer. Suitable monomers or prepolymers may be induced to form afluoropolymer on the surface of the underlying polymer if required. Theessential requirements of the fluorocarbon are that it be soluble, to asufficient degree, in the solvent used and that it impart the desiredcharacteristics to the surface of the underlying polymer when applied bythe process of the invention (or that it be a useful precursor forimparting the desired characteristics).

It may not be necessary for the fluorocarbon only to contain the atomsfluorine and carbon, though it is likely that these atoms willpredominant. Oxygen atoms may be present in some fluorocarbons, as mayhalogens other than fluorine, and hydrogen atoms are not necessarilyexcluded (although perfluorocarbons, in which fluorine atoms take theplace of all hydrogen atom sites, are preferred). Fluorinated elastomers("fluoro-elastomers)" or fluorinated rubbers ("fluoro-rubbers") may beuseful in the invention. Often they are soluble, at least in theirprepolymer form if not in their fully polymerised or cross-linked form,in common solvents. The VITON® fluorinated elastomer available fromDuPont in prepolymer form is soluble in readily available solvents andcan be coated onto a polymer substrate, whereupon it may be cross-linkedto acquire the desired properties.

Among the fluorocarbons most preferred for use in the process of thepresent invention are amorphous fluoropolymers such as copolymers oftetrafluoroethylene andbis-2,2-trifluoromethyl-4,5-difluoro-1,2-dioxole. Such copolymers havethe formula ##STR2## where n and m are integers or other numbersrepresentative of the degree of polymerisation and of the proportions ofthe different monomeric units incorporated in the polymer. Suchcopolymers are available from DuPont under the trade mark TEFLON AF,which typically are soluble to the extent of from 2 to 15% (w/w) incertain solvents. The product TEFLON AF 1600 is preferred; the productTEFLON AF 2400 is also an appropriate one to use but is not quite sopreferred as TEFLON AF 1600 because its solubility characteristics arenot so favourable.

Mixtures of fluorocarbons can also be used in the process of theinvention.

Solvents useful in the process of the invention are those in which thefluorocarbon is soluble to an acceptable degree and which do not haveany unwanted effect on the polymer substrate. The nature of the solvent,whether a single component or a mixture, preferred for use willtherefore depend primarily on the nature of the fluorocarbon to bedeposited on the polymer substrate and, possibly, on the nature of thepolymer substrate itself. As mentioned above, if the fluorocarbon is afluorinated elastomer or fluorinated rubber, a wide variety of commonsolvents may be used; examples include methylethylketone, methylenechloride, carbon tetrachloride and others. If, as is preferred, thefluorocarbon is an amorphous fluoropolymer such as one of those soldunder the trade mark TEFLON AF, then a fluorinated solvent may be used.Suitable fluorinated solvents include perfluoroalkanes (such as C₆ -C₁₀perfluoroalkanes, as exemplified by perfluorohexane (C₆ F₁₄) andperfluoroheptane (C₇ F₁₆)) perfluorocycloalkanes (such as C₆ -C₁₀perfluorocycloalkanes), which optionally may contain tertiary aminoand/or ether functions. Fully fluorinated cyclic ethers and otherperfluoro compounds may also be used.

Among the best fluorinated solvents are those available from 3M UnitedKingdom plc, Bracknell, Berkshire, under the FLUORINERT trade mark.These liquids, which are completely fluorinated organic compounds, wereoriginally marketed for specialised applications in the electronicsindustry, but are particularly suitable for use in the presentinvention. The various FLUORINERT liquids vary in their physical andchemical characteristics. Those having a kinematic viscosity at 25° C.of 1.0 cs or below are preferred, as are those having an averagemolecular weight of 500 or below, and those having a vapour pressure of10 torr and above. The FLUORINERT liquids satisfying these criteriainclude those known by the product designations FC-87, FC-72, FC-84,FC-77, FC-104 and, most preferred of all, FC-75.

The concentration of the fluorocarbon in the solvent may typically be inthe range of 0.05% to 0.5% (w/w), with 0.075% to 0.2% (w/w) beingpreferred and about 0.1% (w/w) being optimal. Concentrations below 0.05%may in some circumstances not give completely reliable coverage, whileat concentrations above 0.5% the amount of fluorocarbon may begin toaffect the handling properties of the coated polymer in some instances.

The solution of the fluorocarbon in the solvent may be brought intocontact with the polymer in any convenient way, depending on the natureof the polymer or the article formed from it. Immersion will often bepreferred, but the solution may be sprayed or brushed onto the polymerif appropriate.

The contact time between the solution and the polymer is notparticularly critical but should in general be sufficient to allowcomplete wetting of the polymer surface. A contact time of between 15seconds and 1 minute (such as about 30 seconds) has been found to bequite adequate. It is preferred, though, for the polymer to be dipped inor otherwise brought into contact two or more times with the solutionand to be allowed to dry between dippings. A better covering may beachieved this way. The time between dips will vary with dryingconditions but at room temperature (25° C.) may be in the region of 10to 60 minutes (for example about 30 minutes).

After contact (or final contact) with the solution, the polymer is driedto remove solvent. A drying time of from 10 to 60 minutes, as indicatedabove, is likely to be satisfactory at room temperature. The solvent maybe recovered for future use if desired.

No particularly unusual conditions are needed for carrying out theprocess of the invention. For good adherence of the fluorocarbon to thepolymer substrate, though, the polymer should be clean and free ofgrease. This may be achieved by solvent cleaning either at roomtemperature or in a Soxhlet apparatus. Suitable cleaning solventsinclude chloroform, trichloroethylene or other chlorinated orchlorofluorinated solvents which do not have a deleterious effect on thepolymer. As an alternative, plasma or glow discharge cleaning could beused (for example adapting the cold plasma processes known in the artand previously discussed): the adherence of the fluorocarbon to thepolymer may be increased in this way.

For the invention to work optimally, the process should be carried outin a clean, particle-free environment. This will be routine, though, inthe case of the production of surgical grafts such as vascular grafts.

As will be apparent from what has already been said, the invention hasparticular application in the production of vascular grafts, which arepreferably constructed of knitted polyester yarn (although other porousstructures can be used). After the graft has been knitted, and after theprocess of the invention has been applied to the graft, it is muchpreferred for the graft to be sealed prior to being packaged andsterilised. Sealing the graft prior to packaging enables the surgeon todispense with the otherwise necessary step of sealing the graft bypre-clotting it with the patient's own blood. Collagen, albumin andalginate may be used to seal the graft, but it is preferred to usegelatin and, in particular, gelatin at least part of which has beentreated to reduce the number of amino groups in it: such a sealingprocess is disclosed in EP-A-0183365. The gelatin coating serves tocontrol the rate at which the graft becomes permeable.

The process of the invention can be accurately controlled to providereproducible coatings on bare polymer structures. The chemical structureof the deposited fluorocarbon is homogeneous and physically it is hardand abrasion resistant.

A graft made by the process of the present invention consists basicallyof the pure polymer encased in a fluorocarbon coating which is notthrombogenic so that the graft has all the strength of the pure polymerbut since the polymer is, in use of the graft, isolated from the bloodpassing through the graft it does not display the thrombogenicity of agraft made from the polymer alone.

According to a second aspect of the invention, there is provided anarticle, particularly a vascular graft, comprising a polymer on which afluorocarbon has been deposited by solvent deposition.

The graft is preferably formed from fabric. Best results are obtainedfrom the use of knitted fabric, particularly warp knitted fabric.

Other preferred features of the second aspect are as for the firstaspect mutatis mutandis.

The invention will now be illustrated by the following examples.

EXAMPLE 1

Spools of DACRON TYPE 56 yarn (2×44/27) are placed in a Karl Meyerdouble bed Raschel knitting machine, where two fibres of yarn are warpknitted with 60 needles per inch into seamless long continuous(straight) vascular grafts of 8 mm internal diameter. The continuousgrafts are then formed into same-sized lots and transferred to a Class10,000 clean room. Here they are weighed, inspected for gross defects,washed and cut to 30 cm lengths. The grafts are externally supported bythe application of a 0.9 mm APPRYL 3020 SM3 polypropylene helical coilmelt bonded onto the outer surface. (APPRYL 3020 SM3 is a trade mark ofAppryl SNC, Puteaux, France and is available from Ato Chemicals,Newbury, United Kingdom.) After the external support has been applied,the grafts are re-inspected, trimmed and then given a furtherinspection.

265.5 mg of TEFLON AF 1600 (copolymer of tetrafluoroethylene andbis-2,2-trifluoromethyl-4,5-difluoro-1,2-dioxole) powder, as supplied byDuPont, is dissolved in a plastic beaker in 150 ml of FLUORINERT FC75fluorinated liquid, as supplied by 3M. The FLUORINERT FC75 liquid has arelative density at 25° C. of 1.77, so 150 ml of liquid weighs 265.5 g.The TEFLON AF 1600 powder is allowed to dissolve fully to produce a 0.1%(w/w) solution.

A 30 cm long, externally supported, knitted graft, as produced above, isdipped into the solution at room temperature for 30 seconds. Excesssolution is removed and the graft is allowed to dry for 10 to 60 minutesin air. The graft is then re-dipped and finally dried.

Once dry, the fluorinated vascular graft is gelatin-sealed by followingthe procedure of Example 1 of EP-A-0183365 in a wet-process clean room.The sealed graft is then packaged and sterilised with ethylene oxide.

EXAMPLE 2

Using essentially the same knitting technology as is described inExample 1, a flat sheet of fabric is produced by knitting DACRON TYPE 56yarn. The sheet is cut into 2.5 cm×2.5 cm squares, which are trimmed andinspected as given above in Example 1. The fabric squares are thencoated with TEFLON AF 1600, as described in Example 1 above, and putaside for future use.

EXAMPLE 3

A 30 cm long, 8 mm internal diameter, vascular graft, as prepared inExample 1, was implanted as a thoraco-abdominal bypass in a caninemodel. As a control, a similarly prepared but unfluorinated graft wasalso implanted. Both fluorinated and unfluorinated grafts were implantedfor various lengths of time, ranging from 4 hours to 6 months; explantswere then examined. Preliminary observations clearly demonstrated a moreextensive cellular coating with endothelial-like cells of the luminalsurface of the fluorinated grafts. For example, a fluorinated graftimplanted for 1 month showed excellent healing with a smooth andglistening flow surface, with cells visible. In contrast, an untreatedgraft which had been implanted for six months still demonstrated redthrombi in the middle of the graft, even after that length of time.

EXAMPLE 4

Five 2.5 cm×2.5 cm pieces of fluorinated knitted fabric, as produced inExample 2, were incubated with 3 ml of heparinsed plasma, obtained fromone of four human volunteers, for 1 hour. As a control, similar piecesof unfluorinated material were similarly tested.

To assess the extent of complement activation, the levels of iC₃ b inthe plasma were then estimated using a QUIDEL (trade mark) iC₃ b enzymeimmunoassay. All test materials were pre-wetted by dipping twice in 100%absolute alcohol, twice in 50% alcohol, twice in distilled water andtwice in isotonic saline. The results are shown in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        iC.sub.3 b Values (μg/ml)                                                              Volunteer number Mean                                                         1     2       3      4     Values                                 ______________________________________                                        Non-fluorinated Fabric                                                                      11760   6990    4970 1050  6193                                 Fluorinated Fabric                                                                           3620   2450    1920 5390  3345                                 ______________________________________                                    

Although the results from volunteer number 4 are somewhat anomalous, thedata overall clearly show a marked reduction of complement activationfor the fluorinated fabric, when compared to the non-fluorinated fabric.Complement activation is believed to lead to hyperplasia, which cantherefore be reduced by means of the present invention.

EXAMPLE 5

From 2.5 cm×2.5 cm fabric squares, as prepared in Example 2, wereprepared 1 cm square fabric disks. As controls, non-fluorinated, butotherwise similar, fabric disks were prepared.

Freshly taken human blood, containing 10% (v/v) of 3.8% (w/v) tri-sodiumcitrate was spun for 15 minutes at 900 rpm in polystyrene centrifugetubes. The platelet-rich plasma was removed using siliconised glassPasteur pipettes and put into a polystyrene container, where it wasallowed to rest for 1 hour at 37° C. An equal volume of filtered (0.2μm) phosphate-buffered saline (PBS) was added.

To test each 1 cm square disk, 2 ml of the plasma/PBS mix and the diskwere put into a 7 ml polystyrene bijou bottle, which was rotated gentlyfor I hour at 37° C. After incubation, 0.5 ml of test or control plasmawas taken and made up to 20 ml with filtered PBS. Platelets were countedon a COULTER ZM (trade mark) particle counter, on standard settings. Theresults were as follows:

    ______________________________________                                        Non-fluorinated fabric                                                                             43% depletion                                            Fluorinated fabric    4% depletion                                            ______________________________________                                    

The results show that grafts made from the fluorinated fabric are lesslikely to lead to platelet adhesion on the graft wall and thereforelikely to be less thrombogenic than the untreated fabric.

We claim:
 1. A process for forming a fluorinated surface on a polymer,the process comprising the steps of:a) forming a solution ofperfluorocarbon in a solvent for the perfluorocarbon wherein the solventis selected from the group consisting of perfluoroalkanes,perfluorocycloalkanes and mixtures thereof; b) bringing the solutioninto contact with the polymer surface; and c) removing the solvent fromthe solution in contact with the polymer surface.
 2. The process asclaimed in claim 1, wherein the solvent additionally contains a tertiaryamine function.
 3. The process as claimed in claim 1, wherein thesolvent additionally contains a tertiary ether function.
 4. A processfor forming a fluorinated surface on a polymer, the process comprisingthe steps of:a) forming a solution of an amorphous fluorinated copolymerof tetrafluoroethylene andbis-2,2-trifluoromethyl-4,5-difluoro-1,2-dioxole, in a solvent for theamorphous fluorocarbon; b) bringing the solution into contact with thepolymer surface; and c) removing the solvent from the solution incontact with the polymer surface.
 5. A process as claimed in claim 1,wherein the polymer is in the form of a surgical graft.
 6. A process asdefined in claim 1, wherein the polymer is in the form of a vasculargraft.
 7. A process as claimed in claim 1, wherein the polymer is in theform of a surgical graft and wherein said graft is sealed after formingthe fluorinated surface.
 8. A process as claimed in claim 1, wherein thepolymer is in the form of a surgical graft and wherein said graft issealed with a gelatin after forming the fluorinated surface.